Anticonvulsant activity of two metabotropic glutamate Group I antagonists selective for the mGlu5 receptor: 2-methyl-6-(phenylethynyl)-pyridine (MPEP), and (E)-6-methyl-2-styryl-pyridine (SIB 1893)

The selective mGlu5 antagonists, MPEP, 2-methyl-6-phenylethynyl-pyridine, and SIB1893, (E)-6-methyl-2-styryl-pyridine, have been evaluated as antiepileptic drugs in DBA/2 mice and lethargic mice. Clonic seizures induced by the selective mGlu5 agonist, (R,S)-2-chloro-5-hydroxyphenylglycine (CHPG), 3 mu mol intracerebroventricularly (i.c.v.), are potently suppressed by both compounds (MPEP, ED50=0.42 [0.28-0.62] mg/kg intraperitoneally (i.p.); SIB 1893 ED50=0.19 [0.11-0.33] mg/kg i.p.). Clonic seizures induced by the mGlu1,5 agonist, 3,5-dihydroxyphenylglycine (DHPG), 1.5 mu mol i.c.v., are less potently suppressed by both compounds (MPEP, ED50=22 [13-38] mg/kg i.p., 110 [67-180] nmol i.c.v.; SIB1893, ED50=31 [18-54] mg/kg i.p., 95 [82-110] nmol i.c.v.). Sound-induced seizures in DBA/2 mice are suppressed at 15 min by MPEP and SIE 1893 (MPEP ED50 clonic seizures=18 [10-32] mg/kg i.p., 93 [69-125] nmol i.c.v.; tonic seizures=6.1 [4.5-8.3] mg/kg i.p., 46 [26-80] nmol i.c.v.; SIB 1893 ED50 clonic seizures=27 [17-44] mg/kg i.p., 825 [615-1108] nmol i.c.v., tonic seizures=5.4 [3.4-8.6] mg/kg i.p., 194 [113-332] nmol i.c.v.). The EDS, for MPEP for impaired rotarod performance is 128 [83-193] mg/kg i.p., at 15 min, i.e. a therapeutic index for sound-induced seizures of 5-20. In lethargic mice (lh/lh), a genetic absence model, MPEP, 50 mg/kg i.p., caused a marked reduction in the incidence of spontaneous spike-and-wave discharges. These selective antagonists of mGlu5 block seizures due to activation of mGlu5 at very low systemic doses. At rather higher doses they block convulsive and non-convulsive primary generalised seizures. (C) 2000 Elsevier Science Ltd. All rights reserved.